The alkaloids obtainable from Vinca rosea (Catharanthus rosea) have constituted a most productive source for drugs which adversely affect the growth of experimental malignancies in mammals. Initially, only some of the alkaloids obtainable from the leaves of the plant by extraction and purifiable by chromatography were found to be active. It has been found that all these active anti-neoplastic Vinca alkaloids obtained directly from the plant are dimeric indole-dihydroindole alkaloids which can be represented by the formula: ##STR1##
In the above formula where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vinblastine (vincaleucoblastine, VLB) is represented; where R.sup.1 is acetoxy, R.sup.2 is formyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vincristine (leurocristine) is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl, R.sup.4 is hydroxy, and R.sup.5 is H, leurosidine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl or formyl, R.sup.3 is ethyl and R.sup.4 and R.sup.5 taken together form an .alpha.-epoxide ring, leurosine and leuroformine, respectively are represented. Literature references to the above alkaloids are as follows: leurosine (U.S. Pat. No. 3,370,057), VLB (U.S. Pat. No. 3,097,137), leuroformine (Belgian Pat. No. 811,110); leurosidine (vinrosidine) and vincristine (both in U.S. Pat. No. 3,205,220).
Two of the above alkaloids, vinblastine and vincristine, are now marketed for the treatment of malignancies, particularly the leukemias and related diseases, in humans. The two marketed alkaloids are customarily administered by the iv route. Two others, leurosidine and leuroformine, have been on clinical trial in the United States or in Europe.
Chemical modification of the Vinca alkaloids started slowly for several reasons. In the first place, the molecular structures involved are extremely complex, and chemical reactions which modify one specific functional group of the molecule without affecting other groups have been difficult to develop. Secondly, dimeric alkaloids lacking desirable chemotherapeutic properties have been recovered or produced from Vinca rosea extracts, and a determination of their structures has led to the conclusion that these inactive compounds are closely related structurally to, or even isomeric with, an active alkaloid.
One of the more recent, and more successful, modifications of the basic indole-dihydroindole structure has been the preparation of C-3 carboxamide and carboxhydrazide derivatives. Many of these carboxamides are active anti-tumor agents (see U.S. Pat. No. 4,166,810, Barnett et al., J. Med. Chem., 21, 88 (1978), id, 22, 391 (1979). In particular, 4-desacetyl VLB C-3 carboxamide (vindesine) is very active and is currently on clinical trial in humans.
A related approach is described in United States patent 4,096,148 wherein the preparation of various unsubstituted or substituted 3-spiro-5"-oxazolidine-2",4"-dione derivatives of VLB, desacetyl VLB and 4-desacetyl vincristine are described among other compounds. Typical Vinca oxazolidinedione derivatives found in the above patent can be portrayed by the following formula ##STR2## wherein R is H, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.4 alkenyl, CH.sub.2 --CHX--CH.sub.3
or CH.sub.2 --CH.sub.2 X; PA1 X is Br or Cl; PA1 R.sup.1 is OH or ##STR3## R.sup.2 is CH.sub.3 or CHO; one of R.sup.3 and R.sup.4, is OH or H and the other is C.sub.2 H.sub.5.
wherein
According to U.S. Pat. No. 4,096,148, these oxazolidinediones are prepared by reaction of, for example, vinblastine with an isocyanate RNCO (where R is other than H). One of the compounds thus prepared is 3"-(2-chloroethyl)-3-spiro-5"-oxazolidine-2",4"-dione. This compound has proved to be an extremely active anti-neoplastic agent but is also described in the aforesaid patent as being useful as an intermediate--see Col. 7 lines 49-58--for the preparation of the corresponding 3"-(2-thioethyl) derivative. This latter compound is stated to be, in turn, useful as an intermediate in preparing the corresponding N-(.beta.-thioethyl)VLB 3-carboxamide (compound 25 in Conrad et al., loc. cit.).
It is an object of this invention to find improved methods for synthesizing VLB 3"-(.beta.-thioethyl)-3-spiro-5"-oxazolidine-2",4"-dione.